{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:59:06Z","timestamp":1785473946224,"version":"3.56.0"},"reference-count":26,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Big Data for Smart Society (GATE) Institute","award":["This research is part of the GATE project funded by the Horizon 2020 WIDE-SPREAD-2018\u20132020 TEAMING Phase 2 program under grant agreement no. 857155"],"award-info":[{"award-number":["This research is part of the GATE project funded by the Horizon 2020 WIDE-SPREAD-2018\u20132020 TEAMING Phase 2 program under grant agreement no. 857155"]}]},{"award":["This research is part of the GATE project funded by the Horizon 2020 WIDE-SPREAD-2018\u20132020 TEAMING Phase 2 program under grant agreement no. 857155"],"award-info":[{"award-number":["This research is part of the GATE project funded by the Horizon 2020 WIDE-SPREAD-2018\u20132020 TEAMING Phase 2 program under grant agreement no. 857155"]}],"id":[{"id":"https:\/\/ror.org\/01d16s529","id-type":"ROR","asserted-by":"publisher"}]},{"name":"FNOI","award":["This research is part of the program \u201cResearch, Innovation and Digitalization for Smart Transformation\u201d 2021\u20132027 (PRIDST) under grant agreement no. BG16RFPR002-1.014-0010-C01"],"award-info":[{"award-number":["This research is part of the program \u201cResearch, Innovation and Digitalization for Smart Transformation\u201d 2021\u20132027 (PRIDST) under grant agreement no. BG16RFPR002-1.014-0010-C01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Variant-based pathogenicity predictors such as REVEL evaluate missense variants in isolation, discarding the gene-length and allele-frequency context needed to compare collections of genes. Methods: We introduce a composite gene-level metric integrating Hardy\u2013Weinberg heterozygosity, coding-sequence length, and REVEL scores. The metric returns a single value per gene expressing variant burden per unit of coding sequence within a given cohort, so that the ratio between a case and a control cohort quantifies gene-level enrichment. It was evaluated on 55 high-confidence autism genes, defined as the intersection of three large-scale ASD sequencing studies, against the 1000 Genomes reference. Results: It identifies elevated pathogenic burden in 48 of 55 genes, removes gene-length and variant-count confounds, and substantially outperforms naive gene-level aggregation of REVEL scores. Bootstrap resampling and a label-permutation control confirm the enrichment is stable and not an artefact of the scoring construction. Conclusions: The metric allows genes to be ranked within a set and aggregate burden to be compared across gene sets. We present it as a complementary gene-level layer for case\u2013control and gene-set comparisons, with a nonlinear successor outlined as future work.<\/jats:p>","DOI":"10.3390\/genes17080892","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:53:31Z","timestamp":1785333211000},"page":"892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Risk Beyond the Variant: A Composite Metric for Autism Gene Pathogenicity"],"prefix":"10.3390","volume":"17","author":[{"given":"Beloslava","family":"Malakova","sequence":"first","affiliation":[{"name":"GATE Institute, Sofia University, 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5383-3030","authenticated-orcid":false,"given":"Simeon","family":"Karpuzov","sequence":"additional","affiliation":[{"name":"GATE Institute, Sofia University, 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7231-7060","authenticated-orcid":false,"given":"Dobromir","family":"Tsolyov","sequence":"additional","affiliation":[{"name":"GATE Institute, Sofia University, 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0205-585X","authenticated-orcid":false,"given":"Georgi","family":"Petkov","sequence":"additional","affiliation":[{"name":"GATE Institute, Sofia University, 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milen","family":"Zamfirov","sequence":"additional","affiliation":[{"name":"Faculty of Educational Sciences and Arts (FNOI), Sofia University, 1574 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s00787-012-0359-5","article-title":"Autism spectrum disorders","volume":"22","author":"Lauritsen","year":"2013","journal-title":"Eur. 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